2D QSAR Studies on Series of Human Beta-secretase (BACE-1) Inhibitors

Abstract

β -secretase (BACE-1) plays a pivotal role in the β-Amyloid plaques formation, which is responsible for progressive cognitive and memory loss commonly found in Alzheimer disease patients. As a consequence, it has been considered as a good target for drug development efforts. Early work focused on the synthesis of peptidomimetics, but poor pharmacokinetics profile prevented advancing lead compounds to clinical trials. As an alternative, aminoimidazoles, aminohydantoins and aminopyridines derivatives that inhibit BACE-1 were designed. Herein we report statistically sound descriptor- based (r2 = 0.87, q2 = 0.85, 6 PCs) and fragment-based (r2 = 0.91, q2 = 0.84, 6 PCs) QSAR models, that show high predictive ability (r2pred = 0.84, averaged r2m=0.78) and underscore polar interactions that are important for BACE-1 inhibition.